The present invention encompasses compositions used in the medical and veterinary sciences. In particular, intravenous compositions, especially those used for parenteral nutrition, are improved by coadministration with antifungal/antibacterial agents.
Fungi and bacteria are ubiquitous. Fortunately, most bacteria and fungi remain non-pathogenic to humans and lower animals unless they somehow become introduced into the bloodstream of lymphatic system. However, once internalized, massive infestation throughout the body can result. Bacterial sepsis can usually be treated successfully with antibiotics, although a complete treatment regimen can be expensive and time consuming. Moreover, bacterial strains which are resistant to antibiotics are becoming a serious problem. Mycotic (fungal, mold, yeast) infections, which are typically occasioned by extremely high fevers, are unusually refractive to standard therapeutic agents used to combat bacterial infections and often result in death of the patient.
Intravenous administration of solutions of various types to humans and lower animals is required in the treatment of a variety of disease states. Yet, the risk of bacterial or mycotic contamination and sepsis is especially acute during i.v. therapy. It is now becoming widely recognized that prolonged administration of intravenous solutions, which involves repeated changes of exhausted solution reservoirs, removal and re-insertion of catheters, and other physical manipulations and adjustments of the intravenous apparatus, can lead to whole body mycotic and/or bacterial contamination and infections if sterile conditions are not rigorously maintained. Recent investigations have demonstrated that bacterial or fungal contaminants are present in many supposedly sterile i.v. solutions being used in hospitals.
Physicians have long decried the fact that progress in developing new treatment regimens for burn victims, comatose patients, patients who have undergone gastrointestinal surgery, cancer victims, and other patients who require intravenous feeding is being hindered by the problem of sepsis. The following references illustrate the current state of the medical art in this area.
"Infection is a significant hazard, and disseminated fungal infection has been a particularly frequent and dread complication of total parenteral nutrition."--Goldmann and Maki, "Infection Control in Total Parenteral Nutrition", Journal of American Medical Association, 223, 12 (1973), pp. 1360-64.
"Disseminated candidiasis is an increasingly common cause of morbidity and death, especially in hospital patients . . . "--Letter to the Editor, The Lancet, Nov. 13, 1976, p. 1084.
At least 10,000,000 hospital patients receive i.v. therapy yearly. Septicemia rates as high as 8% are seen in some hospitals.--Maki, "Preventing Infection in Intravenous Therapy", Hospital Practice, April, 1976, pp. 95-104.
"On the clinical front the approach to infection with yeasts is far less purposeful; and this is well illustrated by Candida, which is evidently an increasingly common cause of morbidity and death, especially in hospital patients."--"Troublesome Candida", The Lancet, July 26, 1975, at 167.
C. albicans was identified as the causative microbial species in 8 of 13 cases of parenteral septicemia.--Curry and Quie, "Fungal Septicemia in Patients Receiving Parenteral Hyperalimentation", NEJM, 285, 22 (1971), pp. 1221-25.
The likelihood that unused i.v. devices are contaminated is small. "However, once they are in use, contamination is another matter. The 35 percent contaminations [in this study] suggest that this complication may occur with ease."--Duma, et al., "Septicemia from Intravenous Infusions", NEJM, 284, 5 (1971), pp. 257-60.
" . . . [T]he indwelling catheter which is necessary for the delivery of the concentrated glucose solution . . . may be a route by which direct contamination can occur." [456]--Ashcraft and Lepe, "Candida Sepsis Complicating Parenteral Feeding", JAMA, 212, 3 (1970), pp. 454-46.
Seventy-four hospital i.v. needles tested; 24 were infested with microorganisms, including Candida; infestation increased with increasing duration of needle placement.--Lowenbraun, et al., "Infection from Intravenous `Scalp-Vein` Needles in a Susceptible Population", JAMA, 212, 3 (1970), pp. 451-53.
Seven-month period; 3 patients on i.v. develop secondary bloodstream infection originating from the site of catheter insertion; 2 die.--Darrell and Garrod, "Secondary Septicaemia from Intravenous Cannulae", British Medical Journal, May 24, 1969, pp. 481-82.
Amphotericin to treat Candida in i.v. therapy.--Brennan, et al., "Prolonged Parenteral Alimentation: Candida Growth and the Prevention of Candidemia by Amphotericin Instillation", Ann. Surg., 172, Sept. 1972, p. 265.
"The risks [of i.v. feeding] appear unacceptably high . . . can hyperalimentation be made safe?--It is unfortunate that answers are not available."--Editorial, NEJM, 285, 22 (1971), pp. 1258-59.
So patients sicken and die, not because the manufacturers of intravenous solutions are negligent, but because once the product passes from the skilled, sophisticated hands of the specialist to the hands of a possibly indifferent, less well educated, overworked hospital employee, manipulative problems and inattention to detail lead to massive infection.
Physicians are currently meeting this problem by curtailing, or even discontinuing, prolonged use of i.v. feeding. They recognize that, once the patient does become infected, the normal treatment regimen for the patient's original illness must be interrupted to fight the hospital-induced infection with a potent antibiotic and, if the patient somehow survives that, only then can treatment of the patient's original problem be resumed.
The present invention is based on the discovery that certain carboxylate antimicrobial agents solve the dual problems of mycotic and bacterial sepsis associated with the use of i.v. solutions. It is to be understood that the use of carboxylate anitmicrobials in the manner of this invention is prophylactic (i.e., to prevent mycotic or bacterial contamination which could result in infection) rather than therapeutic (i.e., to cure an established disease).
When properly used, the preferred carboxylates disclosed herein are so effective that they can constitute at least a partial substitute for the heat- or filtration-sterilization procedures normally used in the manufacture of intravenous solutions, and the like, with the added advantage that the carboxylates maintain sterility even during use situations where sterility can be lost.